Ethers, secondary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto

Abstract

The present invention pertains to certain compounds of Formula (Ia) and pharmaceutical compositions thereof that modulate the activity of the 5-HT2A serotonin receptor. Compounds and pharmaceutical compositions thereof are directed to methods useful in the treatment of platelet aggreagation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, blood clot formation, asthma or symptoms thereof, agitation or a symptom thereof, behavioral disorders, drug induced psychosis, excitative psychosis, Gilles de la Tourette's syndrome, manic disorder, organic or NOS psychosis, psychotic disorder, psychosis, acute schizophrenia, chronic schizophrenia, NOS schizophrenia and related disorders, and sleep disorders, sleep disorders, diabetic-related disorders, progressive multifocal leukoencephalopathy and the like. The present invention also relates to the methods for the treatment of 5-HT2A serotonin receptor associated disorders in combination with other pharmaceutical agents administered separately or together.

What is claimed is: 
     
       1. A method for modulating the activity of a 5-HT 2A  serotonin receptor by contacting the receptor with N-[4-[2-(2-hydroxy-ethylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide, or a pharmaceutically acceptable salt thereof, comprising administering to an individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of N-[4-[2-(2-hydroxy-ethylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
       2. A method for modulating an activity of a 5-HT 2A  serotin receptor by contacting the receptor with N-[4-[2-(2-hydroxy-ethylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide
 wherein the N-[4-[2-(2-hydroxy-ethylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide is generated as a result of a metabolic chemical reaction of 3-methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide.   
     
     
       3. A method for treating a 5-HT 2A  associated disorder in an individual comprising administering to the individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of N-[4-[2-(2-hydroxy-ethylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
       4. A method for treating a 5-HT 2A  associated disorder in an individual comprising administering to the individual in need thereof a therapeutically effective amount of N-[4-[2-(2-hydrox)-ethylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide,
 wherein the N-[4-[2-(2-hydroxy-ethylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide is generated as a result of a metabolic chemical reaction following administration of 3-methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy) phenyl)benzamide, or a pharmaceutically acceptable salt thereof, to the individual.   
     
     
       5. A method for reducing platelet aggregation in an individual comprising administering to the individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of N-[4-[2-(2-hydroxy-ethylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
       6. The method of  claim 5 , wherein the individual has coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, or a symptom of any of the foregoing. 
     
     
       7. A method of reducing platelet aggregation in an individual comprising administering the individual in need thereof a therapeutically effective amount of N-[4-[2-(2-hydroxy-ethylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide,
 wherein the N-[4-[2-(2-hydroxy-ethylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide is generated as a result of a metabolic chemical reaction following administration of 3-methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy) phenyl)benzamide, or a pharmaceutically acceptable salt thereof, to the individual.   
     
     
       8. The method of  claim 7 , wherein the individual has coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, or a symptom of any of the foregoing. 
     
     
       9. A method for reducing risk of blood clot formation in an angioplasty or coronary bypass surgery patient, or a patient suffering from atrial fibrillation, comprising administering to the individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of N-[4-[2-(2-hydroxy-ethylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
       10. A method of reducing risk of blood clot formation in an angioplasty or coronary bypass surgery patient, or a patient suffering from atrial fibrillation, comprising administering to the individual in need thereof a therapeutically effective amount of N-[4-[2-(2-hydroxy-ethylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide,
 wherein the N-[4-[2-(2-hydroxy-ethylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide is generated as a result of a metabolic chemical reaction following administration of 3-methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy) phenyl)benzamide, or a pharmaceutically acceptable salt thereof, to the individual.   
     
     
       11. A method for treating a 5-HT 2A  serotonin receptor associated disorder in an individual comprising administering to the individual in need thereof a pharmaceutical composition comprising a therapeutically effective amount of N-[4-[2-(2-hydroxy-ethylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
       12. A method for treating a 5-HT 2A  serotonin receptor associated disorder in an individual comprising administering to the individual in need thereof a therapeutically effective amount of N-[4-[2-(2-hydroxy-ethylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide, or a pharmaceutically acceptable salt thereof,
 wherein the N-[4-[2-(2-hydroxy-ethylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide is generated as a result of a metabolic chemical reaction of 3-methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide, or a pharmaceutically acceptable salt thereof.   
     
     
       13. The method according to claim 3, wherein said 5-HT 2A  mediated disorder is sleep disorder. 
     
     
       14. The method according to claim 3, wherein said 5-HT 2A  mediated disorder is progressive multifocal leukoencephalopathy. 
     
     
       15. The method according to claim 3, wherein said 5-HT 2A  mediated disorder is hypertension. 
     
     
       16. The method according to claim 3, wherein said 5-HT 2A  mediated disorder is pain. 
     
     
       17. The method according to claim 3, wherein said 5-HT 2A  mediated disorder is claudication. 
     
     
       18. The method according to claim 3, wherein said 5-HT 2A  mediated disorder is peripheral artery disease. 
     
     
       19. The method according to claim 3, wherein said 5-HT 2A  mediated disorder is vasoconstriction. 
     
     
       20. The method according to claim 3, wherein said 5-HT 2A  mediated disorder is vasospasm. 
     
     
       21. The method according to claim 3, wherein said 5-HT 2A  mediated disorder is thrombosis. 
     
     
       22. The method according to claim 6, wherein said 5-HT 2A  mediated disorder is stroke.